Hormone Therapy Fails in TBI Trials

No benefit for progesterone seen at 6 months.

by John Gever John Gever,Managing Editor, MedPage Today
December 16, 2014

Action Points

Note that two large trials evaluating the use of progesterone to improve functional outcomes in patients with traumatic brain injury failed to show that the hormone had a benefit.

Be aware that these results stand in contrast to earlier, smaller studies but are considered more definitive.

Progesterone treatment failed to help patients with severe acute traumatic brain injury (TBI) in two large, independent trials -- in stark contrast to the positive results seen in two earlier trials.

In one of the new multicenter, placebo-controlled trials, which was stopped prematurely for futility, there was no difference in the likelihood of favorable neurological and functional outcomes at 6 months in 882 randomized patients (relative benefit of progesterone 0.95, 95% CI 0.85-1.06, P=0.35), and rates of phlebitis and thrombophlebitis were three times as common with progesterone versus placebo, according to David W. Wright, MD, of Emory University in Atlanta, and colleagues.

These results were replicated closely in a separate multinational trial involving 1,195 patients: 50.4% of those assigned to progesterone achieved favorable 6-month outcomes compared with 50.5% of the placebo group, reported Brett E. Skolnick, PhD, at North Shore University Hospital in Manhasset, N.Y., and colleagues.

In an accompanying editorial, Lee Schwamm, MD, of Massachusetts General Hospital in Boston, argued that the negative results should not have been a complete surprise. He characterized the effect sizes seen in the earlier, smaller trials as relatively modest and, despite statistically significant P-values, potentially the result of chance.

Schwamm said the phase III failures may be indicative of "a fundamental bias in the current practice of scientific inquiry," in which investigators move too eagerly from limited phase II studies into larger and longer trials.

"Slower-than-expected enrollment, overly optimistic effect sizes, better-than-expected performance in the placebo groups, and sample-size estimates that were based on one of multiple efficacy outcomes in small safety trials are commonly observed patterns in failed trials," he wrote, and most of these were present in the progesterone studies.

At least to an extent, Skolnick and colleagues agreed, writing that the failures "should stimulate a rethinking of procedures for drug development and testing in TBI." They acknowledged that TBI is complex and often poorly characterized in the clinic, objective biomarkers are largely lacking, and clinical outcome measures are insensitive.

For their part, Wright and colleagues simply threw up their hands. They argued that they had taken what they believed were appropriate steps to ensure that the trial would find a benefit if one existed. Although reducing the heterogeneity in injury type could make trials easier to design for success, it would "come at the cost of more homogenous pathological findings and decreased generalizability of the results," they noted.

Schwamm recommended that the trialist community should take more care at the phase II stage, performing more extensive and sequential studies before embarking on large pivotal trials. He said this would make phase II more expensive and time-consuming, but with the benefit of fewer costly failures at the phase III stage.

Background and Study Details

Impetus for the trials came initially from bench studies and animal studies suggesting that progesterone has neuroprotective functions that could aid recovery from serious head injuries. It originates in the nervous system, and a host of lab studies have shown that it inhibits cerebral edema and neuronal damage and death, and promotes functional recovery.

In the U.S. trial, the salient benefit was in 30-day neurologic outcome; the Chinese trial found benefits in 6-month mortality and Glasgow Outcome Scale score, a categorical index of functional ability.

However, as Schwamm noted, both trials had multiple outcome measures, and not all of them showed an advantage for progesterone.

For the phase III trials, both groups used 6-month Glasgow scores for their primary outcomes. Also in both trials, patients were accepted into the trial if they had severe TBI (Glasgow Coma Scale scores of 8 or less in the study by Skolnick's group; 4 to 12 in the study by Wright's group). Treatment was initiated within hours of injury, with progesterone or placebo given by infusion over 4 to 5 days.

There was no suggestion of benefit in either study. In addition to no difference in Glasgow Outcome Scale between groups at 6 months, mortality rates were similar, and there were no specific subgroups of patients defined by injury severity or type of ancillary treatment such as surgery who appeared to do significantly better than others.

Neither investigator group nor Schwamm suggested that it would be worth testing progesterone again in severe TBI with different treatment parameters or patient characteristics.

Reaction

After the findings were released, shock in the TBI community was almost palpable.

"No one was sadder than I was when I heard that the drug wasn't showing a benefit," said Kurt Denninghoff, MD, of the University of Arizona, who served as "hub principal investigator" at one of the 21 sites in the trial led by Wright.

The question now churning among TBI researchers is: How could the two phase III trials have yielded a negative result when there was so much other evidence that progesterone is helpful. "That's one of the things we're reflecting on now, as a community," said Denninghoff.

Researchers are now casting a new, critical eye on how such treatments are evaluated in clinical trials. "Perhaps the measures we use aren't good enough to tell us that someone has responded to treatment," Denninghoff told MedPage Today.

Stein, whose lab at Emory University laid much of the preclinical groundwork for the human studies, took aim specifically at the Glasgow Outcome Scale, which is commonly used in the clinic to grade patients' clinical status in the months following stroke and TBI.

In an email to MedPage Today, Stein characterized the Glasgow scale as "a set of very blunt, nonquantitative, patient-reported, subjective 'yes-or-no' answers to seven to nine questions."

He said this approach "is not the most effective way to go about determining the real functional status of a patient with brain injury," noting that patient self-reports have "a lot of issues" that should disqualify them as the basis for primary outcome measures.

Denninghoff and Stein also suggested that patient selection could be reconsidered. Stein said advanced imaging technologies such as diffusion tensor imaging "could have been used to help in patient group assignment, and the results could then be coupled with quantitative measures from a test like, to name one among many, the Luria Nebraska Neuropsychological Battery."

That would have been costly, Stein said, but if the recent negative results end up prompting a new round of large trials, such an approach "might have ended up being far less expensive in the long run."

He added, "It is time for more precision to be applied to the planning and development of clinical trials and to the appropriate use of parametric data instead of simplified rating scales."

Some neurologists said they weren't entirely surprised by the trial results. Joshua Cohen, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told MedPage Today in an email that a number of hormones have shown neuroprotective properties in lab studies, but "exogenous" treatment has not been found effective in human patients.

"It may be that a better way to harness the benefits of hormones will be determining a way to stimulate hormone receptor expression in the brain, thus increasing the ability of endogenous hormones to engage in neuroprotective or neurotrophic activity," he said.

Denninghoff said that the two large trials may yet yield a benefit -- in pointing the way toward new studies or new approaches to TBI.

"We've collected biomarkers, we've collected data on all the patients, we've collected information on how they were treated. We have a dataset that now the NIH has allowed us to collect, by giving us the funding to do this, that is going to change the face of traumatic brain injury treatment and research in the future."

The study by Skolnick's group was funded by BHR Pharma, a division of Besins Healthcare.

Skolnick disclosed serving as a vice president of Hillhurst Biopharmaceuticals, which is developing a different potential treatment for TBI. Co-authors disclosed relevant relationships with BHR Pharma/Besins Healthcare.

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